Process for the preparation of podophyllotoxin

ABSTRACT

There are disclosed intermediates which can be converted into podophyllotoxin and related compounds, which are known antineoplastic agents. There are also disclosed processes for the preparation of such intermediates, and processes for the conversion of the intermediates into known intermediates which are readily converted into podophyllotoxin and related compounds.

CROSS REFERENCE TO RELATED APPLICATION

This application is a divisional of U.S. Ser. No. 304,634, filed Feb. 1,1989, now U.S. Pat. No. 5,013,851, which is a divisional of Ser. No.129,795, filed Dec. 7, 1987, now U.S. Pat. No. 4,845,248, which is adivisional of Ser. No. 805,484, filed Dec. 5, 1985, now U.S. Pat. No.4,734,512.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is directed to intermediates which can beconverted into podophyllotoxin and related compounds, which are knownantineoplastic agents. More specifically, this invention relates to anefficient total synthesis of podophyllotoxin. Additionally, the presentinvention provides processes for the preparation of such intermediates,and processes for the conversion of the intermediates into knownintermediates which are readily converted into podophyllotoxin andrelated compounds.

2. Description of the Prior Art

Podophyllotoxin (I), a known lignan lactone isolated from severalspecies of Podophyllum, is a potent cytotoxic agent. Numerous otherrelated compounds having the characteristic aryltetralin ring structure,either naturally occurring or derived from some naturally occurringcompounds are known. Some of these compounds possess antineoplasticactivity while others are useful for conversion to compounds having suchactivity. Podophyllotoxin is an important intermediate for theproduction of the antitumor agent etoposide and its analogues.Podophyllotoxin has the structure shown below: ##STR1##

The key molecular features of podophyllotoxin are (1) presence of theC2-C3 trans lactone, and (2), a cis relationship between the C1 and C2substituents. For the synthesis of etoposide, the C4 hydroxy group canbe either in the α (podophyllotoxin) or the β (epipodophyllotoxin)orientation because in the glycosidation step only the C4 β glycoside isobtained.

In J. Org. Chem., 31, 4004-4008 (1966), W. J. Gensler and C. D. Gatsonisdescribe the completion of the total synthesis of podophyllotoxinthrough the epimerization by enolate quenching of theO-tetrahydropyranyl derivative of picropodophyllin. However, thisepimerization does not proceed to completion, and separation of an about45:55 mixture of podophyllotoxin and picropodophyllin is required.Picropodophyllin which is the cis-lactone isomer of podophyllotoxin hasthe structure: ##STR2##

In J. Org. Chem., 46, 2826-2828 (1981), A. S. Kende et al. report on animproved total synthesis of podophyllotoxin in 12 steps with an overallyield of 4.5% from piperonal. However, the Kende synthesis requires thepreparation and then the subsequent epimerization of picropodophyllinsimilar to the above-mentioned Gensler synthesis.

In J. Am. Chem. Soc., 103, 6208-6209 (1981), D. Rajapaksa and R. Rodrigoreport a new synthesis of podophyllotoxin which avoids the thermodynamichurdle present in the conversion of picropodophyllin to podophyllotoxinas was previously described in the above-mentioned references of Gensleret al. and Kende et al. However, the synthesis requires the preparationof a bicyclic precursor and a satisfactory yield can be achieved only byrecycling procedures.

SUMMARY OF THE INVENTION

The preparation of podophyllotoxin in accordance with the presentinvention also avoids the picropodophyllin intermediate and, inaddition, provides a new and efficient stereospecific synthesis startingwith Gensler ketone of the formula: ##STR3## This invention is based onthe realization that the cis Gensler ketone of the formula ##STR4## hasa finite stability. This stability permits the incorporation of ahydroxymethyl group at C3 without epimerization at C2.

Previously, Kende et al, [J. Amer. Chem. Soc., 99, 7082-7083 (1977) andJ. Org. Chem., 46, 2826-2828 (1981)] and Murphy et al [J. C. S. PerkinsI, 271-276 (1982)] have tried hydroxymethylation at C3 using a base andformaldehyde. This gave mainly the bisalkylation product and the yieldwas not high. The present invention avoids bisalkylation, and gives aproduct with the desired stereochemistry at C2.

The synthesis of podophyllotoxin and related compounds in accordancewith this invention is depicted in Scheme I: ##STR5## wherein R¹ and R²each are independently hydrogen or (lower)-alkoxy, or R¹ and R², takentogether, is methylenedioxy; R³ is hydrogen or a carboxyl-protectinggroup; R⁴ and R⁶ each are independently hydrogen or (lower)alkoxy; R⁵ ishydrogen or a phenol-protecting group; R⁷, R⁸ and R⁹ each areindependently lower(alkyl) or phenyl; and R¹⁰ is hydrogen, lower(alkyl),lower(alkoxy) or nitro.

Compounds V, VI, VII and VIII in Scheme I are novel intermediates.

The terms "(lower)alkyl" and "(lower)alkoxy" as used herein and in theclaims mean unbranched or branched chain alkyl or alkoxy groupscontaining from 1 to 6 carbon atoms such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl, etc. Preferably, thesegroups contain from 1 to 4 carbon atoms and, most preferably, theycontain 1 or 2 carbon atoms. Unless otherwise specified in theparticular instance, the term "halogen" as used herein and in the claimsis intended to include chlorine, fluorine, bromine and iodine.

Carboxyl-protecting groups which can be employed in the presentinvention to block or protect the carboxylic acid function arewell-known to those skilled in the art and include moieties such as(lower)alkyl, phenyl(lower)alkyl, ring substituted phenyl(lower)alkyl,methoxymethyl, benzyloxymethyl, allyl, diphenylmethyl and the like.Phenolprotecting groups which can be employed in the present inventionto block or protect the phenol function are also well-known to thoseskilled in the art and include moieties such as (lower)alkyl,phenyl(lower)alkyl, ring substituted phenyl(lower)alkyl,benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, methoxymethyl, allyland the like. Other suitable protecting groups are disclosed in"Protective Groups in Organic Synthesis", Theodora W. Greene (John Wiley& Sons, 1981), Chapter 3 for phenol and Chapter 5 for carboxyl, whichare hereby incorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION

The aryltetralone starting material, a compound of Formula III, whereinR¹ and R², taken together, is methylenedioxy, R³ is hydrogen, CH₃ or C₂H₅, R⁴ and R⁶ are methoxy, and R⁵ is methyl may be prepared by thegeneral method described in J. Am. Chem. Soc., 82, 1714-1727 (1960), W.J. Gensler et al. Compounds of Formula III may also be prepared by animproved procedure described in J. C. S. Perkin I, 271-276 (1982), W. S.Murphy and S. Wattanasin, in which R¹ is methoxy and R² is hydrogen, orR¹ and R², taken together, is methylenedioxy, R³ is hydrogen or ethyl,R⁴ and R⁶ are hydrogen or R⁴ and R⁶ are methoxy, and R⁵ is methyl.

A compound of Formula III, with the ester radical in the relative transconfiguration, is epimerized to a cis aryltetralone of Formula IV at lowtemperatures, i.e., from about -80° C. to -20° C., and preferably atabout -78° C., by enol quenching utilizing a non-nucleophilic strongbase such as lithium hexamethyldisilazide, sodium methylsulfinylmethide,lithium 1,1,6,6-tetramethylpiperide and lithium diisopropylamide in aninert organic solvent such as tetrahydrofuran (THF), dioxane,dimethoxymethane, hexamethylphosphoramide and tetramethylurea and thenadding a mineral acid, for example, hydrochloric acid. This is reactionA of Scheme I.

Reaction B of Scheme I illustrates the preparation of the enol silylether, a compound of Formula V, from a compound of Formula IV. This isaccomplished by reacting a compound of Formula IV with a reagent havingthe formula: ##STR6## wherein R⁷, R⁸, and R⁹ are as previously definedand X is a halogen atom or a trifluoromethanesulfonate group. Thereaction is conducted at a temperature of from -78° C. to 25° C. in thepresence of a non-nucleophilic base. To avoid epimerization at C2, themildest possible conditions should be employed. The silyl reagent XI maybe, for example, trimethylsilyl trifluoromethanesulfonate (TMSOTf),trimethylsilyl iodide, t-butyl-dimethylsilyl iodide or triethylsilyliodide.

A compound of Formula V may be converted to a compound of Formula VI,reaction C in Scheme I, without purification or isolation of a compoundof Formula V. This is accomplished by reacting a compound of Formula Vwith a bisbenzyloxymethane having the formula: ##STR7## or abenzyloxymethyl halide having the formula: ##STR8## wherein R¹⁰ is thesame as previously described and X is halogen. This reaction isconducted in the presence of a Lewis acid such as TMSOTf, ZnCl₂, ZnBr₂,and TiCl₄. The reaction should be conducted at a temperature of fromabout -50° C. to 20° C. and preferably at about 0° C.

A compound of Formula VI is converted to a compound of Formula VIII byreduction of the C4 carbonyl group at a temperature of from -20° C. to20° C. using a reducing agent such as LiBH₄, NaBH₄, NaBH₃ CN, LiBHC₂ H₅,or Zn(BH₄)₂. Compounds of Formula VII are obtained as a by-product ofthis reaction.

Reaction F of Scheme I illustrates the debenzylation of a compound ofFormula VIII to obtain a compound of Formula IX. Debenzylation can becarried out by standard hydrogenating conditions, i.e., by usingcatalysts such as Pt, Raney Ni, Rh and solvents such as THF, ethanol andethyl acetate. This reaction is carried out at a temperature of from 0°C. to 50° C., preferably about 25° C.

A compound of Formula IX is converted to a compound of Formula X(Reaction G of Scheme I) by treatment with an aqueous base followed bytreatment with a condensation reagent, e.g., dicyclohexylcarbodiimide,1-cyclohexyl-3-(2-morpholinoethyl)-carbodiimidemetho-p-toluenesulfonate, isopropyl chloroformate, etc. This reaction iscarried out at a temperature of from about 0° C. to about 50° C.,preferably about 25° C.

In accordance with the process of this invention, the C2 anion will notepimerize because it is tied back as a lactone and once the lactone isopened up, the carboxylate salt will suppress deprotonation at C2.

DESCRIPTION OF SPECIFIC EMBODIMENTS

In the following examples 1-6, melting points were recorded on aThomas-Hoover capillary melting point apparatus and are uncorrected.Proton NMR spectra were recorded on Bruker WM 360 spectrometer usingtetramethylsilane as an internal standard. Infrared spectra weredetermined on Nicolet 5DX FT IR spectrophotometer. Chromatographicseparation was carried out using Woelm silica gel (0.040-0.063 mm) inflash chromatography or 0.5 mm E. Merck silica gel plates (60F-254).

EXAMPLE 1 d,l cis-Ethyl1,2,3,4-tetrahydro-6,7-methylenedioxy-4-oxo-1-(3,4,5-trimethoxyphenyl)naphthalen-2-carboxylate,(IVa), (Compound IV wherein R¹ and R², taken together, =methylenedioxy,R³ =C₂ H₅, R⁴ and R⁶ =OCH₃ and R⁵ =CH₃)

nBuLi solution in hexane (1.7M, 16.5 mL, 28 mmol) was added dropwise at-78° C. to a solution of diisopropylamine (3.94 mL, 28 mmol) in 10 mL ofTHF. After 20 minutes of stirring at -78° C., a THF solution of IIIa(compound III wherein R¹ -R⁶ are as defined in the title of thisexample) (3.0 g, 7.0 mmol) was added. The solution was warmed to -40° C.for 1 hour and then treated with concentrated HCl solution (5 mL ofconcentrated HCl diluted to 10 mL with THF). The reaction mixture wasdiluted with ice water and extracted with ethyl acetate. Drying over Na₂SO₄ and removal of the solvent gave white solid. This was recrystallizedfrom hot ethanol to give 2.11 g (70%) of the title compound; mp146°-148° C.: NMR (CDCl₂) δ 1.22 (t, 3H, J= 7 Hz), 2.74 (dd, 1H, J=18.1,4.2 Hz), 2.93 (dd, 1H, J=18.0, 13.3 Hz), 3.72 (s, 6H), 3.80 (s, 3H),4.10 (m, 2H), 4.66 (d, 1H, J=4.7 Hz), 6.03 (s, 1H), 6.04 (s, 1H), 6.17(s, 2H), 6.62 (s, 1H), 7.54 (s, 1H); IR (KBr) 1731, 1674, 1590, 1504,1481, 1255, 1130, 1038, cm⁻¹.

Anal. calcd. for C₂₃ H₂₄ O₈.0.25H₂ O: C,63.81; H,5.70; Found: C,63.59;H,5.43.

EXAMPLE 2 d,l cis Ethyl(1,2-dihydro-6,7-methylenedioxy-4-trimethylsilyloxy-1-(3,4,5-trimethoxyphenyl)naphthalen-2-carboxylate,(Va), (Compound V wherein R¹ and R², taken together, =methylenedioxy, R³=C₂ H₅, R⁴ and R⁶ =OCH₃, R⁵ =CH₃ and R⁷, R⁸ and R⁹ =CH₃

To a solution of IVa (856 mg, 2 mmol) in 10 mL of dry CH₂ Cl₂ were addedat 3° C. triethylamine (304 mg, 3 mmol) andtrimethylsilyltrifluoromethanesulfonate (TMSOTf, 667 mg, 3 mmol). Themixture was stirred at room temperature for 1 hour. The mixture wascooled again and the same quantities of triethylamine and TMSOTf wereadded. The mixture was stirred at room temperature for 1 hour and thenwashed with cold saturated NaHCO₃ solution. The organic layer was driedover Na₂ SO₄ and evaporated to give crude title compound, NMR (CDCl₃) δ0.15 (m, 9H), 1.32 (t, 3H, J=7.321 Hz), 3.76 (s, 6H), 3.78 (s, 3H), 4.01(m, 2H), 4.23 (1H, dd, J=7.439 Hz), 5.17 (d, 1H, J=2.776 Hz), 5.90 (d,1H, J= 9.623 Hz), 6.44 (s, 2H), 6.6 (s, 1H), 7.0 (s, 1H).

EXAMPLE 3 d,l[1α,2α,3β]-Ethyl-1,2,3,4-tetrahydro-6,7-methylendioxy-3-benzyloxymethyl-4-oxo-1-(3,4,5-trimethoxyphenyl)naphthalen-2-carboxylate,(VIa) (Compound VI wherein R¹ and R², taken together, =methylenedioxy,R³ =C₂ H₅, R⁵ and R⁶ =OCH₃, R⁵ =CH₃ and R¹⁰ =H).

A. Crude Va obtained in Example 2 was re-dissolved in 5 mL of CH₂ Cl₂and added at -20° C. to a solution of bisbenzyloxymethane (912 mg, 5mmol) in 10 mL of CH₂ Cl₂ containing 0.1 mL of the TMSOTf solution, (theTMSOTf solution was prepared by dissolving 10 g of TMSOTf in 10 mL ofCH₂ Cl₂). After stirring at room temperature for 18 hours, the reactionmixture was washed with saturated NaHCO₃ solution and dried over Na₂SO₄. Removal of the solvent and a SiO₂ chromatography of the residue (4%ethyl acetate--CH₂ Cl₂) gave 613 mg (70% based on the recovered startingmaterial, 170 mg) of the title compound, mp 107°-109° C.: NMR (CDCl₃) δ1.19 (t, 3H, J=7 Hz), 2.99 (dt, 1H J=12.2 1 Hz), 3.63 (dd, 1H, J=9.2,3.3 Hz), 3.71 (s, 6H), 3.78 (s, 3H), 3.83 (dd, 1H, J=12.5, 5.0 Hz), 4.01(m, 2H), 4.30 (dd, 1H, J=9.0, 2.3 Hz), 4.36 (d, 1H, J=12.2 Hz), 4.50 (d,1H, J=12.1 Hz), 4.56 (d, 1H, J=5.1 Hz), 6.01 (s, 1H), 6.02 (s, 1H), 6.10(s, 2H), 6.59 (s, 1H), 7.29 (m, 5H), 7.55 (s, 1H); IR (KBr) 1733, 1672,1590, 1560, 1532, 1250, 1130, 1035 cm⁻¹.

Anal. calcd. for C₃₁ H₃₂ O₉.0.25H₂ O: C, 67.32; H, 5.92, Found: C,67.24; H, 5.93.

B. To a solution of IVa (140 mg, 0.33 mmol) in 5 ml of CH₂ Cl₂ wereadded at 0° C. triethylamine (55 μl, 0.40 mmol) and TMSOTf (80 μL, 0.40mmol). After 0.5 hours of stirring at 0° C., the same quantities oftriethylamine and TMSOTf were added. The reaction mixture was washedwith saturated NaHCO₃ solution after 0.5 hours of additional stirring.The CH₂ Cl₂ layer was dried over Na₂ SO₄ and evaporated to give crudeVa. This material was redissolved in 5 mL of CH₂ Cl₂ and cooled to -78°C. After addition of benzyloxymethyl chloride (100 mg, 0.8 mmol), TiCl₄(44 μL, 0.4 mmol) was added dropwise. Stirring was continued at -78° C.for one hour and at room temperature overnight. The reaction mixture wasdiluted with CH₂ Cl₂ and washed with brine. The residue obtained afterdrying over Na₂ SO₄ and evaporation of the solvent was chromatographedon SiO₂ (5% EtOAc--CH₂ Cl₂) to give 85 mg of VIa (74% yield based on therecovered starting material, 50 mg). This material was identical to theproduct obtained in part A of this example by NMR and mass spectroscopy.

EXAMPLE 4 d,l [1α,2α,3β,4α]-Ethyl1,2,3,4-tetrahydro-6,7-methylenedioxy-3-benzyloxymethyl-4-hydroxy-1-(3,4,5-trimethoxyphenyl)naphthalene-2-carboxylate,(VIIa), (Compound VII wherein R¹ and R², taken together=methylenedioxy,R³ =C₂ H₅, R⁴ and R⁶ =OCH₃, R⁵ =CH₃ and R¹⁰ =H) and Neopodophyllotoxinbenzyl ether, (VIIIa), (Compound VIII wherein R¹ and R², takentogether=methylenedioxy, R³ =C₂ H₅, R⁴ and R⁶ =OCH₃, R⁵ =CH₃ and R¹⁰ =H)

To a solution of Compound VIa (400 mg, 0.55 mmol) in 5 mL of dry THF at0° C. was added at 0.6 mL of LiBH₄ solution (2M in THF). After stirringat room temperature, the reaction was quenched by addition of asaturated NH₄ Cl solution. The product was extracted with ethyl acetate,and the ethyl acetate layer was dried over Na₂ SO₄. The residue obtainedafter evaporation of the solvent was chromatographed on SiO₂ plates (10%ethyl acetate-CH₂ Cl₂) to give 120 mg (43%) of the second titlecompound, i.e., neopodophyllotoxin benzyl ether, mp 194°-196° C. NMR(CDCl₃) δ 2.96 (t, 1H, J=4.5 Hz), 3.25 (m, 1H), 3.39 (dd, 1H, J=7.9, 7.5Hz), 3.55 (dd, 1H, J=7.4, 7.2 Hz), 3.71 (s, 6H), 3.83 (s, 3H), 4.10 (d,1H, J=4.6 Hz), 4.45 (s, 1H), 5.16 (d, 1H, J=4.8 Hz), 5.96 (s, 2H), 6.21(s, 2H), 6.42 (s, 1H), 6.71 (s, 1H), 7.29 (m, 5H); IR (KBr) 1775, 1590,1508, 1485, 1330, 1255, 1125 cm⁻¹.

Anal. calcd. for C₂₉ H₂₈ O₈ . H₂ O: C, 66.65; H, 5.77; Found: C, 66.70;H 5.54.

A more polar band yielded 70 mg (25%) of the first title compound(VIIa), NMR (CDCl₃) δ 1.08 (t, 3H, J=7.1 Hz), 2.75 (m, 1H), 2.99 (dd,1H, J=11.9, 5.4 Hz), 3.50 (t, 1H, J=8.5 Hz), 3.68-3.89 (m, 4H), 3.75 (s,6H), 3.80 (s, 3H), 4.27 (d, 1H, J=5.5 Hz), 4.49 (d, 1H, J=12.0 Hz), 4.57(d, 1H, J=12.0 Hz), 4.77 (d, 1H, J=7.7 Hz), 5.90 (s, 1H), 5.91 (s, 1H),6.23 (s, 2H), 6.38 (s, 1H), 7.07 (s, 1H), 7.33 (m, 5H). Compound VIIamay be converted to Compound VIIIa in the presence of mild base.

EXAMPLE 5 Neopodophyllotoxin, (IXa), (Compound IX wherein R¹ and R²,taken together, =methylenedioxy, R⁴ and R⁶ =OCH₃ and R⁵ =CH₃)

A solution of compound VIIIa (80 mg, 0.16 mmol) in 10 mL of ethylacetate containing a few drops of methanol and 40 mg of 10% Pd/C washydrogenated under 30 psi of H₂ at room temperature for 3 hours. Afterfiltration through celite the solvent was removed to give a white solid.This material was chromatographed on SiO₂ plates (CH₂ Cl₂) to give 36 mg(55%) of the title compound, mp 235°-237° C.: NMR (CDCl₃ δ 3.02 (t, 1H,J=4.5 Hz), 3.17 (m, 1H), 3.67 (t, 1H, J=4.8 Hz), 3.76 (m, 1H), 3.78 (s,6H), 3.85 (s, 3H), 4.25 (d, 1H, J=4.7 Hz), 5.18 (d, 1H, J=4.8 Hz), 5.95(d, 1H, J=1.0 Hz), 5.97 (d, 1H, J=1.0 Hz, 6.27 (s, 2H), 6.49 (s, 1H),6.74 (s, 1H); IR (KBr) 3425, 1764, 1592, 1508, 1489, 1333, 1255, 1240,1125, 1037 cm⁻¹.

Anal. calcd. for C₂₂ H₂₂ O₈.0.5 H₂ O: C, 62.40; H, 5.47; Found: C,62.34; H, 5.22.

EXAMPLE 6 Podophyllotoxin, (Xa), (Compound X wherein R¹ and R², takentogether, =methylenedioxy, R⁴ and R⁵ =OCH₃ and R⁵ =CH₃)

Neopodophyllotoxin (IXa) (33 mg, 0.08 mmol) was dissolved in 1 mL of THFand 2 mL of water, and treated with 0.2 mL of 1N NaOH solution at roomtemperature for 2.5 hours. The resulting solution was cooled andacidified with 1N HCl solution. It was extracted rapidly with ethylacetate and the ethyl acetate layer was washed with brine and dried overNa₂ SO₄. The residue obtained after evaporation of the solvent wasdissolved in 2 mL of dry THF and treated with dicyclohexylcarbodiimide(25 mg, 0.12 mmol) at an ice bath temperature for 2 hours. The resultingmixture was evaporated and chromatographed on SiO₂ plates (20% ethylacetateCH₂ Cl₂) to give 15 mg (45% of the title compound; mp 234°-236°C. NMR (CDCl₃) δ 1.99 (d, 1H, J=8.1 Hz), 2.77-2.87 (m, 2H), 3.76 (s,6H), 3.81 (s, 3H), 4.09 (t, 1H, J=9 z), 4.59 (d, 1H, J+5.1 Hz), 4.61 (t,1H, J=6.9 Hz), 4.77 (t, 1H, J=8 Hz), 5.97 (d, 1H, J=1.2 Hz), 5.98 (d,1H, J=1.2 Hz), 6.37 (s, 2H), 6.51 (s, 1H), 7.11 (s, 1H); IR (KBr) 3420,1765, 1592, 1508, 1485, 1240, 1130 cm⁻¹.

Anal. calc'd. for C₂₂ H₂₂ O₈.0.25 H₂ O: C, 63.08; H, 5.41; Found: C,63.00; H, 5.33.

We claim:
 1. A process for the preparation of podophyllotoxin whichcomprises:(a) treating cis-ethyl 1,2,3,4,-tetrahydro-6,7-methylenedioxy-4-oxo-1-(3,4,5-trimethoxyphenyl)naphthalen-2-carboxylatewith hexamethyldisilazane and trimethylsilyl iodide to obtain thecorresponding enol silylether; (b) reacting said enol silylether withbisbenzyloxymethane in the presence of a catalytic amount oftriethylsilyl triflate to obtaind,l[1α,2α,3β]-ethyl-1,2,3,4-tetrahydro-6,7-methylenedioxy-3-benzyloxymethyl-4-oxo-1-(3,4,5-trimethoxyphenyl)naphthalen-2-carboxylate;(c) reducing the C4 carbonyl group of said d,l[1α,-2α,3β]-Ethyl-1,2,3,4-tetrahydro-6,7-methylenedioxy-3-4-oxo-1-(3,4,5-trimethoxyphenyl)naphthalen-2-carboxylateto obtain neopodophyllotoxin benzyl ether; (d) hydrogenating saidneopodophyllotoxin benzyl ether to give neopodophyllotoxin; and (e)hydrolyzing said neopodophyllotoxin and treating with a condensationreagent to yield podophyllotoxin.